Monthly Archives: February 2021

The speakers will discuss what is currently known about genomic drivers of heart failure and opportunities for novel therapeutics being explored in their own research programs.

TORONTO (PRWEB) February 02, 2021

Heart failure is a significant global health issue. More than half of the people who develop heart failure die within five years. Current treatments do not help the largest group of these patients those with heart failure with preserved ejection fraction (HFpEF) and have limited effectiveness for those with reduced injection fraction (HFrEF).

HFpEF has been called the greatest unmet need in cardiovascular disease given the number of heart failure deaths per year and the proportion of patients with HFpEF. Despite significant research into the drivers of heart failure, many patients remain undiagnosed or poorly managed and new therapies are needed.

This webinar will cover recent advances in heart failure genomics with a focus on translating findings into improved therapeutics and diagnosis. Genuity Science and their colleagues are building large-scale real-world datasets combining whole-genome sequencing and detailed longitudinal clinical data from thousands of participants. For heart failure, these datasets help scientists discover and validate new drug targets for heart failure and are enriched with participants with HFpEF. Additionally, the speakers will discuss what is currently known about genomic drivers of heart failure and opportunities for novel therapeutics being explored in their own research programs.

Join guest speakers Benoit Tyl, MD, FESC, Medical and Scientific Director, Cardiology, Servier; Marc Semigran, MD, Senior Vice President, Medical Sciences, Myokardia; Irene Blat, PhD, Senior Director of Data Products and Analytics, Genuity Science; and webinar host Ellen Gordon, PhD, Vice President, Business Development, Genuity Science for the live webinar on Tuesday, February 23, 2021 at 10am EST (3pm GMT/UK).

For more information, or to register for this event, visit Genomic Advances in Heart Failure.

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Genomic Advances in Heart Failure, Upcoming Webinar Hosted by Xtalks - PR Web

Genome sequencing can teach us a huge amount about a species, and now scientists have completed the sequence for one of the weirdest and most intriguing animals in the world. The Australian lungfish is a living fossil from the time our ancestors first crawled out of the oceans, and its genome reveals that its our closest living fish relative and it has the largest genome of any animal sequenced so far.

The Australian lungfish is one of six lungfish species in the world, and its a bizarre creature. As the name suggests, it has a lung in its back that lets it breathe air, and it can walk along the riverbed like a salamander thanks to its fleshy, well-formed pectoral and pelvic fins.

With those two features working together, the Australian lungfish likes to crawl out of its home in rivers and freshwater pools and venture onto dry land. Its not truly amphibious, but it has been known to live out of water for several days at a time provided its skin doesnt dry out too much.

Thats a throwback to one of the most important steps in evolutionary history, when the first animals crawled out of the oceans onto dry land during the Devonian period, some 420 million years ago. The Australian lungfish is one of the closest living relatives to those pioneering sea creatures, and because its remained largely unchanged by evolution for well over 100 million years, its genome potentially preserves insights into that key period.

So scientists in Europe set out to sequence that complete genome. This has already been done for many animals, plants and microbes of interest, including humans, mice, worms, mosquitoes, Tasmanian tigers, sharks, apples, tomatoes, wheat, barley, and the Black Death bacteria.

It turns out that the Australian lungfish has the largest genome of any animal ever sequenced, containing around 43 billion DNA nucleotides. Thats 14 times bigger than the human genome, and quite a leap above the previous record holder, the axolotl, on 32 billion.

The team found that the staggering size mostly came down to repetition. About 90 percent of the lungfish genome was made up of repeating sequences, which can have variable positions in the genome. In this respect, the team says the lungfish actually more closely resembles land vertebrates than other fish.

With the genome fully sequenced, the researchers were able to confirm that the lungfish is the closest living fish relative of all tetrapods, the absolutely gigantic group of land animals containing everything with the familiar body structure of four limbs coming off a central trunk. That means reptiles, birds, and mammals, including humans.

In fact, were more similar than you might think. The genes that control embryonic development of the lungfishs lungs are the same ones as in humans, which show that the evolution in both species can be traced to the same origin. The development of the bones in their fins is also controlled by the same genes as those of our hands.

The team also discovered some genomic pre-adaptions to life on the land. The lungfish genome had expanded in areas linked to air breathing, limb development, reproduction, and the ability to smell the air.

All up, sequencing the genome of the Australian lungfish will help improve our understanding of one of the most important transitions in evolutionary history.

The research was published in the journal Nature.

Source: University of Konstanz

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"Living fossil" genome sequence reveals clues to evolution of life on land - New Atlas

Precision surveillance combining genomic sequencing and conventional surveillance was able to delineate a large nosocomial influenza A virus (IAV) outbreak and map the source to a single patient. The findings from this investigation, published in Clinical Infectious Diseases, revealed the source of the outbreak was not health care workers (HCWs) as was initially believed.

Over 12 days in early 2019, 89 HCWs and 18 inpatients within a single hospital were identified as cases of influenza-like illness, triggering the investigation. During this investigation, 91 inpatients and 290 HCWs were screened via temperature checks, symptom surveys, and molecular testing for IAV, influenza B, and respiratory syncytial virus. Of these, 18 patients (19.8%) and 89 HCWs (29.7%) tested positive for IAV.

The HCWs testing positive were distributed across 29 different work assignments and 87 of the 89 (>90%) were vaccinated with the quadrivalent seasonal influenza virus vaccine 2 to 5 months before diagnosis (average: 108 days). Investigators highlight that most of these HCWs had minor symptoms not normally classified as influenza-like illness due to the absence of fever. This prompted the removal of fever as a requirement from the investigations case definitions.

Complete genomic sequences were obtained for 214 IAV isolates, 126 from the original hospital where investigation and surveillance were performed and 88 from a second hospital undergoing surveillance only. Comparison revealed a cluster of 66 isolates differing by 3 or fewer single-nucleotide variants (SNVs), suggesting a single viral clone was behind the outbreak.

The outbreak cluster was identified as influenza A H1N1pdm09 and was found in 43 HCWs and 17 inpatients. All HCWs included in this cluster had been vaccinated. Outbreak virus strains with representative variants, 5 in total, were cultured for functional characterization and did not show antigenic drift. A further analysis of genomes from cases identified by the conventional investigation during days 0 to 3 of the outbreak and the mining of electronic records provided a timeline of the earliest 9 cases. An interaction network based on available contact records found that almost all cases trace back to these 9 cases and identified the origin as a single patient and a few interactions in the emergency department.

Biospecimens from 22 HCWs whose tests were performed at labs outside of the health system in question were unavailable, limiting the investigation results. Also, only partial genomes were recovered from 2 specimens linked to the epidemiological outbreak investigation.

According to investigators, enhanced screening and isolation of emergency department patients with respiratory symptoms, even when not their primary complaint, are important steps to mitigating outbreaks. Also, better recognition by leadership that HCW transmission can occur with mild symptoms along with improved education of staff to avoid working while ill and extended sick leave were recommended by investigators. Finally, the investigators believe these findings are applicable to a range of respiratory pathogens, including SARS-CoV-2, and that implementation of precision surveillance will be critical for identification and mitigation of nosocomial outbreaks.

Disclosure: One study author declared an affiliation with Sema4.

Reference

Javaid W, Ehni J, Gonzalez-Reiche AS, et al. Real-time investigation of a large nosocomial influenza A outbreak informed by genomic epidemiology. Clin Infect Dis. Published online November 30, 2020. doi:10.1093/cid/ciaa1781

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Nosocomial Influenza Outbreak Investigation Informed by Genomic Analyses - Infectious Disease Advisor

Majority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa.

We addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype.

The investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa.

The study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.

BioMed research international. 2021 Jan 13*** epublish ***

Tarun Karthik Kumar Mamidi, Jiande Wu, Chindo Hicks

Center for Computational Genomics and Data Science, Departments of Pediatrics and Pathology, University of Alabama-Birmingham School of Medicine, Birmingham, Alabama 35233, USA., Department of Genetics and the Bioinformatics and Genomics Program, Louisiana State University Health Sciences Center, School of Medicine, 533 Bolivar Street, New Orleans, LA 70112-1393, USA.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/33511206

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Elucidation of the Genomic-Epigenomic Interaction Landscape of Aggressive Prostate Cancer. - UroToday

Image: Transcriptomes heatmap example. Credit:Thomas Shafee/Wikimedia Commons, CC by 4.0

The field of genomics has been revolutionised by the breadth of data available and the development of artificial intelligence (AI) techniques that are powerful enough to process this information.

AI has been a key focus at the Festival of Genomics & Biodata since its launch in 2016. Over the years, our scientists have presented on the latest techniques in machine learning, which is a type of AI that finds and learns from patterns in statistics and data.

Dr Anguraj Sadanandam leads the Systems and Precision Cancer Medicine team at the ICR and applies his multidisciplinary experience both in the wet-lab and computational biology to identify and test personalised therapies for different cancer types.

He says, Machine learning may be considered a new buzzword to some, but its been applied by researchers for a very long time. I have been working in this space over the last 15 years.

Dr Sadanandam will speak about "Precision Oncology Through Data Orchestration, Artificial Intelligence and Clinical/Preclinical Therapeutics" on 29 January as part of the AI stream of the Festival of Genomics & Biodata.

Previously, genomic data was the bottleneck and researchers would have to work with what was available. Now, there is a wealth of genomic data, which covers all genes and their variants. Researchers can also combine this with other -omics data ranging from proteomics, which examines data from proteins, to radiomics, which is based on data from medical radiology images, as well as clinical income information from patients.

Going forward Dr Sadanandam says context is key. Researchers and clinicians need to be able to integrate various pieces of information to develop personalised cancer treatments. In the future, he said he hopes that when a patient comes in with a tumour, a doctor could look at it and tell them what the progression of that tumour could be 10 years from now.

Dr Sadanandams lab has harnessed AI for cancer treatment in a number ways including PhenMap, a new tool for personalised cancer medicine.

PhenMap uses machine learning to identify cancer subtypes and biomarkers based. Dr Sadanandam likens PhenMaps approach to asking a question from the clinical and biological perspectives in parallel. PhenMap, short for phenotype mapping, starts by looking at patient prognosis and treatment responses, known as phenotypes. At the same time, PhenMap looks at biological data this could be genomics or other data. Next, it integrates both sets of data to create integrated groupings of patients. These new categories are more distinct and could potentially identify patients who might benefit from certain treatments as well as new targets for drugs.

In a recent study, Dr Sadanandams team showed PhenMap could identify clinically-relevant subtypes and biomarkers in breast cancer. These subtypes were associated with specific drug responses to an inhibitor currently in development. Researchers used data from mRNA in breast cancer cell lines and patient samples, though PhenMap could be applied to different types of data and other cancers. The tool also works with single cell samples rather than bulk tumour sequencing making it more accessible and suitable to the clinic.

AI tools like PhenMap help targeted cancer treatment become more personalised. Scientists have been able to group people with cancer into subtypes, but machine learning can pick up more complicated patterns and narrow these groups.

PhenMap groups patients in two ways: into discrete subgroups and as individuals along a spectrum. While a doctor may say a patient is in stage 1 or stage 3, AI tools could help pinpoint patients on a scale of 1 to 100, for example.

The greatest challenge in developing the next generation of personalised cancer treatments for patients is not more data or more powerful algorithms.

Dr Sadanandam says, We are now in a situation with an overwhelming amount of methods and techniques that can find a solution, but the real hurdle is making sure youre getting the right information and then can take it to the clinic. As fast as artificial intelligence is evolving, the treatment protocols are not evolving.

There are findings from other AI tools like PhenMap that could potentially be used in the clinic. However, it takes time for these findings and related technologies to gain regulatory approval and become licensed for patient use. Similarly, AI tools may identify new biomarkers, but validating them in the lab and developing clinical trials can take years.

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Science Talk - AI and the genome: What's next for precision cancer treatment? - The Institute of Cancer Research

WASHINGTON, Feb. 2, 2021 /PRNewswire/ --The Access to Comprehensive Genomic Profiling Coalition (ACGP) announced today the addition of NeoGenomics, Inc. (NASDAQ: NEO) and Tempus to its coalition of diagnostics companies and laboratory service providers to advocate for appropriate broad U.S. health insurance coverage of comprehensive genomic profiling (CGP) for patients living with advanced cancer.

NeoGenomics is a premier cancer diagnostics and pharma services company serving oncologists, pathologists, pharmaceutical companies, academic centers, and others with innovative diagnostic, prognostic, and predictive testing.

Tempus, a leader in precision medicine and artificial intelligence, is a technology company that has built the world's largest library of clinical and molecular data and an operating system to make that information accessible and useful to physicians to enable data-driven treatment decisions.

"NeoGenomics' and Tempus' commitment to innovation to help identify the mutations driving advanced cancers make them valuable partners in ACGP's mission to raise awareness about CGP for advanced cancer patients," saidJim Almas, MD, vice president and national medical director of clinical effectiveness atLabcorp, and the chairman of ACGP.

"We are thrilled to be supporting the important mission of ACGP and its goal of raising awareness about the need for a comprehensive genomic profiling approach in clinical diagnosis and treatment therapy decisions," said Douglas VanOort, NeoGenomics' Chairman and Chief Executive Officer. "ACGP's goal of increasing patient access and insurance coverage of CGP resonates with our ongoing investments in CGP testing."

"Tempus' smart diagnostic testing platform provides physicians with the information they need to personalize patient treatment," said Ryan Fukushima, Chief Operating Officer of Tempus. "We believe that all cancer patients should have access to genomic profiling, and ACGP's aim to increase insurance coverage of this critical service aligns well with our mission."

CGP testing performed soon after a diagnosis of advanced cancer better informs medical management, including treatment decisions and patient care, which can improve clinical outcomes. In advocating for coverage of CGP, ACGP will educate health insurers and other healthcare stakeholders about the clinical utility and economic value of CGP.

All companies that offer CGP tests or offer a product with CGP CDx are eligible for consideration of membership in ACGP. If you are interested in learning more about becoming a member, please contact us here.

About NeoGenomics, Inc.

NeoGenomics, Inc. specializes in cancer genetics testing and information services. NeoGenomics provides one of the most comprehensive oncology-focused testing menus in the world for physicians to help them diagnose and treat cancer. The Company's Pharma Services Division serves pharmaceutical clients in clinical trials and drug development.

Headquartered in Fort Myers, FL, NeoGenomics operates CAP accredited and CLIA certified laboratories in Fort Myers and Tampa, Florida; Aliso Viejo, Carlsbad and San Diego, California; Houston, Texas; Atlanta, Georgia; Nashville, Tennessee; and CAP accredited laboratories in Rolle, Switzerland, and Singapore. NeoGenomics serves the needs of pathologists, oncologists, academic centers, hospitalsystems, pharmaceutical firms, integrated service delivery networks, and managed care organizations throughout the United States, and pharmaceutical firms in Europe and Asia.

For more information, visit: http://www.neogenomics.com

About Tempus

Tempus is a technology company advancing precision medicine through the practical application of artificial intelligence in healthcare. Tempus is a technology with one of the world's largest libraries of clinical and molecular data, and an operating system to make that data accessible and useful, Tempus enables physicians to mark real-time, data-driven decisions to deliver personalized patient care and in parallel facilitates discovery, development and delivery of optimal therapeutics. The goal is for each patient to benefit from the treatment of others who came before by providing physicians with tools to learn as the company gathers more data.

For more information, visit: http://www.tempus.com

About the Access to Comprehensive Genomic Profiling Coalition

Access to Comprehensive Genomic Profiling (ACGP) is a collaborative coalition of leading molecular diagnostics companies and laboratories that aims to raise awareness about comprehensive genomic profiling (CGP) for advanced cancer patients.

For more information, visithttp://www.accesstoCGP.com

SOURCE Access to Comprehensive Genomic Profiling

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NeoGenomics and Tempus Join the Access to Comprehensive Genomic Profiling Coalition - PRNewswire

IRVINE, Calif.--(BUSINESS WIRE)--Genomic Testing Cooperative, LCA (GTC) announced today that they are establishing a program offering comprehensive molecular profiling (DNA+RNA) testing to patients with cancer who are affected by cancer disparity and unable to pay due to lack of insurance or lack of coverage of this type of testing. Ethnic and racial minorities, impoverished people, sexual and gender minorities (LGBTQ) are typically affected more negatively with cancer. One of the reasons for this disparity is poor access to precision medicine and exclusion from clinical trials or studies evaluating the potential differences in the biology of their cancer.

GTC molecular profiling will provide the treating physicians and patients with proper diagnosis and classification of the tumor, help in determining prognosis, selecting therapy and in developing a strategy for treatment that is specific for the patient. The molecular profiling report provides information regarding potential clinical trials that will help the patients evaluate their options to participate and be treated in these clinical trials. Participation in this program will increase access of underserved patients and reduce disparity within community-based cancer care. In addition, the data generated from this program will be de-identified and made available to appropriate academic and scientific groups for the purpose of developing more personalized cancer treatment for minority groups of patients.

GTC is committed to donating 5% of its annual testing volume to this program. GTC is also establishing a donation fund allowing others to support this program and to increase the number of patients benefiting from this program. Individual donors and organizations can contribute to this program with 100% of the raised funds being used to pay for the actual cost of testing.

Patients must be nominated for this program by their physicians. Patients with solid tumors or hematologic neoplasms are eligible for testing. Hematologists/Oncologists can download a simple nomination form from the GTC website, fill in the required information and fax or e-mail to GTC. Patients can mention this program to their hematologists/oncologists and request nomination for this program.

Dr. Maher Albitar, GTC Chief Executive Officer and Chief Medical Officer, stated GTC is committed to making cancer molecular profiling available to all patients with cancer. We all know that patients seen in academic centers are different from real-world patients. Minority patients are not adequately represented in the process for developing innovative medicine nor in the implementation of state-of-the-art medicine. As a diagnostic company, we are doing our part by defining the precise molecular abnormalities that can be targeted but having access to the expensive targeted therapy is a different struggle. We are hoping that pharmaceutical companies will join our effort and do their part in providing the appropriate drugs to these patients and will develop a mechanism to recruit them in their clinical trials.

A recent study reported that one-third of disparities in survival between white and black patients with stage IV colorectal cancer is a product of treatment gaps (HemOnctoday, January 21/2021).

For downloading the patient nomination form, donations or more information, please visit our website genomictestingcooperative.com

About Genomic Testing Cooperative, LCA

Genomic Testing Cooperative (GTC) is a privately-owned molecular testing company located in Irvine, CA. The company operates based on a cooperative (co-op) business model. Members of the co-op hold type A shares with voting rights. The company offers its patron members a full suite of comprehensive genomic profiling based mainly on next generation sequencing. Molecular alterations are identified based on rigorous testing with the aid of specially developed algorithms to increase accuracy and efficiency. The clinical relevance of the detected alterations is pulled from numerous databases using internally developed software. Relevance of findings to diagnosis, prognosis, selecting therapy, and predicting outcome are reported to members. The co-op model allows GTC to make the testing and information platform available to members at a lower cost because of a lower overhead. For more information, please visit https://genomictestingcooperative.com/.

Forward Looking Statements

All of the statements, expectations and assumptions contained in this press release are forward-looking statements. Such forward-looking statements are based on the GTC managements current expectations and includes statements regarding the value of comprehensive genomic profiling, RNA profiling, DNA profiling, algorithms, therapy, the ability of testing to provide clinically useful information. All information in this press release is as of the date of the release, and GTC undertakes no duty to update this information unless required by law.

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Genomic Testing Cooperative Establishes a Program to Address Cancer Disparity by Offering Molecular Profiling to Minority Patients without Adequate...

The GlobalDigital Genome Market,byProduct Type (Sequencer & Analyzers, Reagents & Kits, and Sequencing & Analysis Software), by Application (Clinical (Reproductive Health, Oncology, and Others), Forensics, Drug Discovery and Development, and Other Applications), by End User (Hospitals, Diagnostic Centers, Research Institutes, Biotechnology and Pharmaceutical Companies, and Others), and by Region(North America, Latin America, Europe, Asia Pacific, Middle East, and Africa)was valued atUS$ 7.5billionin 2018, and is projected to exhibit a CAGR of10.9%during the forecast period (2018 2026).

Key players in the market are engaged in development of digital genome, owing to greater future prospects of digital genome in the detection of chronic and infectious disease, birth anomalies, drug discovery & development, and diverse clinical applications. Also, market players are adopting inorganic growth strategies to increase their market presence.

Request for a Sample Report of Digital Genome Market:https://www.coherentmarketinsights.com/insight/request-sample/136

For instance, in October 2016, IBM Corporation collaborated with Quest Diagnostics, an American clinical laboratory, launched IBM Watson Genomics, which can be used for Quest Diagnostics. The service is intended to be used for precise medicine for cancer. In December 2017, PerkinElmer collaborated with Neuromuscular Disease Foundation for launching Whole Genome Sequencing research conducted for the rare muscle disease. Furthermore, in July 2018, Google partnered with National Institutes of Health for developing Google Cloud for the biomedical research.

Furthermore, key players in these market are focused on acquisition strategies to expand their geographical presence. For instance, in January 2016, Thermo Fisher Scientific acquired Affymetrix in order to obtain its chips used for genotyping, cytogenetics and gene expression and array-based platforms for around US$ 1.3 billion. In June 2018, Roche made definitive merger agreement to acquire Foundation Medicine, Inc. This merger agreement enable both companies to accelerate the broad availability of comprehensive genome profiling in oncology. In October 2017, Eurofins Scientific signed an agreement to acquire Forensics and Security division of LGC (LGC Forensics).

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Key Takeaways of the Digital Genome Market:

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Technologies in the Emerging Digital Genome Industry | Illumina, PerkinElmer, Pacific Biosciences of California, Thermo Fisher Scientific KSU | The...

Newswise PHILADELPHIAScientists in the Perelman School of Medicine at the University of Pennsylvania have uncovered the molecular causes of a congenital form of dilated cardiomyopathy (DCM), an often-fatal heart disorder.

This inherited form of DCM which affects at least several thousand people in the United States at any one time and often causes sudden death or progressive heart failure is one of multiple congenital disorders known to be caused by inherited mutations in a gene called LMNA. The LMNA gene is active in most cell types, and researchers have not understood why LMNA mutations affect particular organs such as the heart while sparing most other organs and tissues.

In the study, published this week in Cell Stem Cell, the Penn Medicine scientists used stem cell techniques to grow human heart muscle cells containing DCM-causing mutations in LMNA. They found that these mutations severely disrupt the structural organization of DNA in the nucleus of heart muscle cells but not two other cell types studied leading to the abnormal activation of non-heart muscle genes.

Were now beginning to understand why patients with LMNA mutations have tissue-restricted disorders such as DCM even though the gene is expressed in most cell types, said study co-senior author Rajan Jain, MD, an assistant professor of Cardiovascular Medicine and Cell and Developmental Biology at the Perelman School of Medicine.

Further work along these lines should enable us to predict how LMNA mutations will manifest in individual patients, and ultimately we may be able to intervene with drugs to correct the genome disorganization that these mutations cause, said study co-senior author Kiran Musunuru, MD, PhD, a professor of Cardiovascular Medicine and Genetics, and Director of the Genetic and Epigenetic Origins of Disease Program at Penn Medicine.

Inherited LMNA mutations have long puzzled researchers. The LMNA gene encodes proteins that form a lacy structure on the inner wall of the cell nucleus, where chromosomes full of coiled DNA are housed. This lacy structure, known as the nuclear lamina, touches some parts of the genome, and these lamina-genome interactions help regulate gene activity, for example in the process of cell division. The puzzle is that the nuclear lamina is found in most cell types, yet the disruption of this important and near-ubiquitous cellular component by LMNA mutations causes only a handful of relatively specific clinical disorders, including a form of DCM, two forms of muscular dystrophy, and a form of progeria a syndrome that resembles rapid aging.

To better understand how LMNA mutations can cause DCM, Jain, Musunuru, and their colleagues took cells from a healthy human donor, and used the CRISPR gene-editing technique to create known DCM-causing LMNA mutations in each cell. They then used stem cell methods to turn these cells into heart muscle cells cardiomyocytes and, for comparison, liver and fat cells. Their goal was to discover what was happening in the mutation-containing cardiomyocytes that wasnt happening in the other cell types.

The researchers found that in the LMNA-mutant cardiomyocytes but hardly at all in the other two cell types the nuclear lamina had an altered appearance and did not connect to the genome in the usual way. This disruption of lamina-genome interactions led to a failure of normal gene regulation: many genes that should be switched off in heart muscle cells were active. The researchers examined cells taken from DCM patients with LMNA mutations and found similar abnormalities in gene activity.

A distinctive pattern of gene activity essentially defines what biologists call the identity of a cell. Thus the DCM-causing LMNA mutations had begun to alter the identity of cardiomyocytes, giving them features of other cell types.

The LMNA-mutant cardiomyocytes also had another defect seen in patients with LMNA-linked DCM: the heart muscle cells had lost much of the mechanical elasticity that normally allows them to contract and stretch as needed. The same deficiency was not seen in the LMNA-mutant liver and fat cells.

Research is ongoing to understand whether changes in elasticity in the heart cells with LMNA mutations occurs prior to changes in genome organization, or whether the genome interactions at the lamina help ensure proper elasticity. Their experiments did suggest an explanation for the differences between the lamina-genome connections being badly disrupted in LMNA-mutant cardiomyocytes but not so much in LMNA-mutant liver and fat cells: Every cell type uses a distinct pattern of chemical marks on its genome, called epigenetic marks, to program its patterns of gene activity, and this pattern in cardiomyocytes apparently results in lamina-genome interactions that are especially vulnerable to disruption in the presence of certain LMNA mutations.

The findings reveal the likely importance of the nuclear lamina in regulating cell identity and the physical organization of the genome, Jain said. This also opens up new avenues of research that could one day lead to the successful treatment or prevention of LMNA-mutations and related disorders.

Other co-authors of the study were co-first authors Parisha Shah and Wenjian Lv; and Joshua Rhoades, Andrey Poleshko, Deepti Abbey, Matthew Caporizzo, Ricardo Linares-Saldana, Julie Heffler, Nazish Sayed, Dilip Thomas, Qiaohong Wang, Liam Stanton, Kenneth Bedi, Michael Morley, Thomas Cappola, Anjali Owens, Kenneth Margulies, David Frank, Joseph Wu, Daniel Rader, Wenli Yang, and Benjamin Prosser.

Funding was provided by the Burroughs Wellcome Career Award for Medical Scientists, Gilead Research Scholars Award, Pennsylvania Department of Health, American Heart Association/Allen Initiative, the National Institutes of Health (DP2 HL147123, R35 HL145203, R01 HL149891, F31 HL147416, NSF15-48571, R01 GM137425), the Penn Institute of Regenerative Medicine, and the Winkelman Family Fund for Cardiac Innovation.

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Penn Medicineis one of the worlds leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nations first medical school) and theUniversity of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health Systems patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Centerwhich are recognized as one of the nations top Honor Roll hospitals byU.S. News & World ReportChester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nations first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.

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Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder - Newswise